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Novel pyridine derivative and pyrimidine derivative (3)

A technology of compounds and hydrates, applied in drug combinations, cardiovascular system diseases, organic chemistry, etc., can solve problems such as unreported and unrecorded compounds

Inactive Publication Date: 2008-06-11
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the compounds related to the present invention are not described in Patent Documents 12 and 13, and there is no report on the HGFR inhibitory effect of the compounds disclosed in Patent Documents 12 and 13.

Method used

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  • Novel pyridine derivative and pyrimidine derivative (3)
  • Novel pyridine derivative and pyrimidine derivative (3)
  • Novel pyridine derivative and pyrimidine derivative (3)

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0466] This step is a step of obtaining compound (1t) from compound (1ps) (compound (1ps) is compound (1p) and compound (1s) described in [Production method 1-B].). The same method as can be used.

[0467]

[0468] This step is a step of obtaining compound (1u) from compound (1t). The same method as can be used.

[0469]

[0470] This step is the compound (1u) 2 protecting groups " R 102 -O-C(=O)-" and "P" are deprotected to obtain the compound (1x). According to the type of protecting group, the following reactions can be appropriately combined to carry out this step, thereby obtaining the compound (1x), namely Deprotection reactions using acids such as hydrochloric acid and trifluoroacetic acid; deprotection reactions using inorganic bases such as sodium hydroxide and potassium hydroxide; deprotection reactions using tetrabutylammonium fluoride, etc.; by using palladium carbon, palladium hydroxide Such as the deprotection reaction carried out by the catalytic hydrog...

Embodiment

[0647] The compounds of the present invention can be produced, for example, according to the methods described in the following Preparations and Examples. However, these are illustrative examples, and the compounds of the present invention are not limited to the following specific examples in any way.

[0648] Unless otherwise specified, YMCSIL-60-400 / 230W was used as silica gel for purification in the preparation examples and examples.

[0649] In addition, unless otherwise specified, any one of the following two conditions (gradient elution condition 1 or gradient elution condition 2) was used as the LC-MS purification conditions.

[0650] ODS column (CAPCELL PAK C-18)

[0651] Solvent Liquid A Water

[0652] Solvent Liquid B Acetonitrile

[0653] Solvent C liquid 1% trifluoroacetic acid aqueous solution

[0654] Flow rate 30ml / min

[0655] end time 10min

[0656] Gradient elution condition 1

[0657] 0.00min A: 80%, B: 10%, C: 10%

[0658] 7.80min A: 30%, B: 60%, C:...

preparation example 1

[0665] (Preparation Example 1) tert-butyl 3-dimethylaminoazetidine-1-carboxylate

[0666]To a solution of 1-Boc-azetidin-3-one (3.45 g) in methanol (175 ml) was added 2M dimethylamine-tetrahydrofuran solution (21.9 ml), acetic acid (1.73 ml), 10% palladium on carbon ( 2.15 g), stirred at room temperature in a hydrogen atmosphere for 14 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate-saturated aqueous sodium bicarbonate. The combined organic layers were dried over anhydrous sodium sulfate. It was concentrated to obtain the title compound (4.07 g, 101%) as a colorless oil.

[0667] 1 H-NMR spectrum (CDCl 3 )δ (ppm): 1.43 (9H, m), 2.17 (6H, s), 3.01 (1H, m), 3.79 (2H, m), 3.91 (2H, m).

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Abstract

General formula (I) (wherein, R 1 It is a 3- to 10-membered non-aromatic heterocyclic group or the like. R 2 and R 3 for a hydrogen atom. R 4 , R 5 , R 6 and R 7 Same or different, hydrogen atom, halogen atom, C 1－6 Alkyl etc. R 8 for hydrogen atoms, etc. R 9 It is a 3- to 10-membered non-aromatic heterocyclic group or the like. n is an integer of 1-2. X is a group represented by the formula -CH= or a nitrogen atom. ) or their salts or their hydrates have excellent hepatocyte growth factor receptor (HGFR) inhibitory activity, and exhibit antitumor activity, angiogenesis inhibitory activity or cancer metastasis inhibitory activity.

Description

technical field [0001] The present invention relates to novel pyridine derivatives and pyrimidine derivatives or their salts or their hydrates, which have hepatocyte growth factor receptor inhibitory effects, antitumor effects, angiogenesis inhibitory effects, and cancer metastasis inhibitory effects. Background technique [0002] It has been reported that hepatocyte growth factor receptor (hepatocyte growth factor receptor; ”) overexpression (Non-Patent Document 1). It is generally believed that the HGFR expressed in the above-mentioned tumor cells is often stimulated by hepatocyte growth factor (hepatocyte growth factor; hereinafter referred to as "HGF") to cause autophosphorylation of tyrosine kinase in the intracellular region, so it is related to cancer malignancy. (Abnormal proliferation, invasion or metastatic hyperfunction). [0003] In addition, it has been reported that HGFR is also expressed in vascular endothelial cells, and HGF stimulates HGFR to promote the p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75A61K31/4409A61K31/496A61K31/506A61K31/5377A61P35/00A61P35/04A61P43/00C07D239/47C07D401/12
CPCC07D401/14C07D401/12C07D213/75C07D239/47C07D403/12C07D405/12C07D409/14C07D413/14C07D417/14A61P35/00A61P35/04A61P43/00A61P9/00A61K31/4409
Inventor 松岛知广高桥惠子船坂势津雄尾叶石浩白鸟修司
Owner EISIA R&D MANAGEMENT CO LTD
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